Epilepsy Yung-Yang Lin (林永煬), MD, PhD National Yang-Ming University Taipei Veterans General Hospital

Outline Epidemiology Diagnosis Etiologies and Mechanisms Treatment

Epidemiology

The incidence is around 50/100 000/year. Prevalence of active epilepsy is in the range of 5-10/1000. Age-specific incidence rates: a decrease in younger age groups and an increase in persons above 60 years Overall prognosis for seizure control is good and over 70% will enter remission. Increased risk of premature death particularly in patients with chronic epilepsy (Sudden unexpected death )

Diagnosis

History of event Medical history Blood tests Electroencephalography (EEG) Simultaneous EEG and video recordings Brain scanning (CT scan, MRI) - to discover if the patient has symptomatic epilepsy; a structural cause for their seizures PET, SPECT, MRS Magnetoencephalography (MEG)

Etiologies and Mechanisms

Aetiologies of epilepsy Degenerative brain disorder 3.5% Infection 2.5% Neoplasm 4.1% Idiopathic and cryptogenic epilepsy 65.5% Vascular injury 10.9% Trauma 5.5% Congenital causes 8.0%

Symptomatic seizures in different age groups 10 20 30 40 50 60 70 80 90 100 0–4 5–14 15–24 25–44 45–64 65+ Others Proportion of cases (%) Degenerative Cerebrovascular Brain tumour Trauma Infection Development The major causes of new seizures are different in different patient age groups. Seizures that occur in early life commonly result from injuries during birth, from metabolic disorders, as well as from other congenital problems

Seizure triggers In rare cases patients may have one specific trigger that brings on a seizure, for example: Flashing visual stimuli Looking at a particular kind of pattern Hearing a particular piece of music Reading

Status epilepticus In the majority of cases an epileptic seizure ends of its own accord Status epilepticus is a condition characterized by an epileptic seizure that is so frequently repeated or prolonged as to create a fixed and lasting condition It is a medical emergency that requires prompt and appropriate treatment

Electrophysiological basis for epileptic seizures An abnormal synchronous and sustained activity (overexcitation) in a group of nerve cells This group of nerve cells = epileptogenic focus Abnormal interictal activity When this focus recruits surrounding, normal nerve cells into a synchronous pattern of larger abnormal activity (burst firing), there is transition from interictal to ictal activity = SEIZURE

Imbalance between excitation and inhibition Excess excitation Lack of inhibition epileptic seizures epileptic seizures

Hippocampal sclerosis Extensive neuronal loss and gliosis in the areas of CA1 and the hilus but also in other hippocampal regions to varying degrees. (2) Synaptic reorganization, although not necessarily limited to the mossy fibers of the dentate gyrus. (3) Dispersion of the dentate granule cells. (4) Extrahippocampal pathology (i.e.neuronal loss in the neighboring entorhinal cortex and amygdala).

Neural circuits in hippocampal formation input output

Hilar neuronal loss and mossy fiber sprouting Sprouting is classically seen as a response to the loss of neuronal targets: the loss of mossy cells and somatostatin-positive interneurons in the hilus lead to mossy fiber sprouting in the inner and outer molecular layers. Mossy fibers in humans with MTLE and in animal MTLE models: form excitatory recurrent circuits through collaterals synapsing onto granule cell and interneuron dendrites in the supragranular layer and onto new subgranular dendrites in the hilus.

Molecular mechanisms underlying epileptogenesis NMDA receptor activation Group I mGluR activation in CA3 pyramidal neurons TrkB signaling Cross-talk between neurons and astrocytes (synchronous epileptiform activity in CA1 pyramidal neurons)

Activation of NMDA receptors (at postsynaptic sites on dendritic spines) Ca2+ influx CaMKII and calcineurin activation CaMKII calcineurin GluR1 of AMPA receptors internalization of GABAA receptor [Ca2+]i GABA-mediated synaptic inhibition Ca2+-dependent gene expression KCC2 Mossy fiber sprouting Epileptogenesis

TrkB signaling promotes epileptogenesis in kindling

Astrocytes and epileptiform activity Astrogliosis – abnormal shape and increased numbers of astrocytes – is a prominent feature of Ammon’s horn sclerosis. Glu released from neurons can activate mGluR on astrocytes. Glu released from an astrocyte is sufficient to trigger a PDS (paroxysmal depolarizing shift) in neighboring neuron. A novel mechanism for the synchronization of neuronal firing Positive feedback model

Dynamic cross-talk PDS (paroxysmal depolarizing shift) : a brief(250ms) massive membrane depolarization with an accompanying burst of AP. (best cellular marker of an epileptic event)

Treatment

Treatment of underlying causes Trigger avoidance Drug therapy Surgery Ketogenic diet Vagus nerve stimulation Deep brain stimulation Complementary therapies

Medications and action mechanisms

Medication therapy Selection of antiepileptic drugs (AEDs) based on: ‘Standard’ vs ‘new’ drug Spectrum of efficacy Tolerability Pharmacokinetics Mode of action

Generations of AEDs New Standard Phenytoin (PHT), Pfizer Benzodiazepines Clonazepam (CZP) Clobazam (CLB) Barbiturates Phenobarbital (PB) Primidone (PRM) Ethosuximide (ESM), Pfizer Sodium valproate (VPA), Sanofi Synthelabo (Depakine) Carbamazepine (CBZ), Novartis (Tegretol) Phenytoin (PHT), Pfizer (Dilantin) Standard Zonisamide (ZNS), Athena Oxcarbazepine (OCBZ), Novartis(Trileptal) Tiagabine (TGB), Sanofi Synthelabo(Gabatril) Topiramate (TPM), Janssen-Cilag(Topamax) Gabapentin (GBP), Pfizer(Neurontin) Lamotrigine (LTG), GSK(Lamictal) Vigabatrin (VGB), Aventis(Sabril) Felbamate (FBM), Carter-Wallace New

Modes of action Decreased excitation – via blockade of sodium channels, interaction with voltage-sensitive calcium channels or blockade of glutamate receptors. Increased inhibition – via an increase in the concentration of GABA in the synaptic cleft.

Likely outcomes in patients with newly diagnosed epilepsy First drug Success rate 50% Failure rate 50% Alternative monotherapy Success rate 20% Failure rate 30% Dual therapy Success rate 5% Failure rate 25%

Focal resection – the seizure focus is localised and excised (in this case, by a frontal lobectomy) 1. Sub-dural grid used to localise the site of seizure onset 2. Frontal lobectomy of non-dominant hemisphere (red area indicates the extent of resection)

Vagus nerve stimulation

Vagus nerve stimulation Alteration of norepinephrine release by projections of solitary tract to the locus coeruleus Elevated levels of inhibitory GABA related to vagal stimulation Inhibition of aberrant cortical activity by reticular system activation

Deep brain stimulation

Deep brain stimulation Probably mimics that of high frequency DBS for movement disorders Neurons adjacent to stimulating electrodes appear to undergo long term inactivation following stimulation, leading to interruption of pathologic network activity